The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) proposes to build on nine years of experience conducting community-based clinical trials by expanding the clinical network to include 19 units in the United States and 3 international partners in Australia, Canada, and the United Kingdom. Support will be provided from the Statistical and Data Management Center at the University of Minnesota, an Operations Center at Social and Scientific Systems in Rockville, MD and Core CPCRA Laboratories. The reconfigured network has the capability of following a minimum of 5,000 study participants. The CPCRA will compare, in linked randomized trials, the long-term virologic, immunologic, and clinical effectiveness of various antiretroviral treatment strategies beginning with initial therapy through subsequent second-line and salvage regimens. The CPCRA will also study through randomized trials the clinical impact of immunomodulation as an adjunct to antiretroviral therapy; the optimal use of agents for prophylaxis of opportunistic infections in patients who have experienced CD4+ cell rebounds; and adherence interventions. The CPCRA will conduct nested substudies in the core antiretroviral trials, on targeted therapeutic questions such as the metabolic complications of HIV disease and treatment, and the emergence of HIV-1 resistance in different treatment groups. Pathogenesis questions such as the prognostic importance of virologic and immunologic markers will be addressed using stored specimens in the core antiretroviral trials. Standardized modular data collection forms are used across studies and will be used to describe patterns and determinants of clinical disease, drug resistance, adherence, drug toxicities, quality of life, co-infection with hepatitis, and use of HIV treatment. A strong leadership, advised by experienced and already functioning committees, will manage the CPCRA to ensure that studies are conducted in a timely way, high quality data is collected and resources are used efficiently.